Process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene

ABSTRACT

The present invention relates to an improved process for preparing 4-(6-bromohexyloxy)-butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of a base and a phase transfer catalyst, wherein 4-phenylbutanol in a diluent is metered into a mixture consisting of 1,6-dibromohexane, a base, a phase transfer catalyst and a diluent, and the use of the 4-(6-bromohexyloxy)-butylbenzene thus prepared for producing salmeterol in a method known per se.

RELATED APPLICATIONS

Benefit of U.S. Provisional Application Ser. No. 60/386,280, filed onJun. 6, 2002 is hereby claimed, and said application is hereinincorporated by reference.

The present invention relates to an improved process for the manufactureof 4-(6-bromohexyloxy)-butylbenzene by reacting 4-phenylbutanol with1,6-dibromohexane in the presence of a base and a phase transfercatalyst, and the use of the 4-(6-bromohexyloxy)-butylbenzene thusprepared for producing salmeterol in a method known per se.

BACKGROUND TO THE INVENTION

4-(6-Bromohexyloxy)-butylbenzene is a valuable intermediate product forpreparing the active substance salmeterol, which is used as abronchodilator for treating asthma or chronic bronchitis.

According to the teaching of German patent application DE 34 14 752,4-(6-bromohexyloxy)-butylbenzene is obtained by reacting 4-phenylbutanolwith 1,6-dibromohexane with a sodium hydride dispersion as base. Forsafety reasons it is not really possible to carry out production on anindustrial scale using sodium hydride dispersions.

European patent application EP 1 132 373 describes a laboratory processfor producing 4-(6-bromohexyloxy)-butylbenzene in which a mixtureconsisting of 4-phenylbutanol, 1,6-dibromohexane, potassium hydroxideand tetrabutyl ammonium hydrogen sulphate is stirred for 20 hours atambient temperature. However, this laboratory method cannot be carriedout on an industrial scale as the reaction is strongly exothermic,leading to a sharp increase in the reaction temperature, producingresidues which are difficult to stir and secondary products (eliminationproducts) which lower the yield.

The aim of the present invention is thus to provide a process whichmakes it possible to prepare 4-(6-bromohexyloxy)-butylbenzene in goodyields on an industrial scale while avoiding the drawbacks which occurwith the processes known from the prior art.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that4-(6-bromohexyloxy)-butylbenzene can be prepared in good yields and onan industrial scale by reacting 4-phenylbutanol with 1,6-dibromohexanein the presence of a base and a phase transfer catalyst if4-phenylbutanol in a diluent is added to a mixture comprising orconsisting of 1,6-dibromohexane, a base, a phase transfer catalyst and adiluent.

The invention thus relates to an improved process for preparing4-(6-bromohexyloxy)-butylbenzene by reacting 4-phenylbutanol with1,6-dibromohexane in the presence of a base and a phase transfercatalyst, in which 4-phenylbutanol in a diluent is metered into amixture consisting of 1,6-dibromohexane, a base, a phase transfercatalyst and a diluent.

The invention further relates to the use of the4-(6-bromohexyloxy)-butylbenzene prepared by the process according tothe invention for producing salmeterol in a manner known per se.

Preferred embodiments of the process according to the invention areprocesses wherein:

(A) the base used is an alkali metal hydroxide such as lithiumhydroxide, sodium hydroxide or potassium hydroxide, particularlypowdered potassium hydroxide;

(B) the phase transfer catalyst (PTC) used is a tetraalkylammonium ortetraalkylphosphonium salt, wherein the alkyl groups may be identical ordifferent, such as for example salts of tetraoctylammonium,methyltrioctylammonium, tetramethylammonium, tetraethylammonium,tetrahexylammonium Aliquat 175 (tributylmethylammonium) or Aliquat 336(methyltrioctylammonium). Preferably, the PTC is a tetraalkylammoniumhalide, a tetraalkylammonium sulphate, a tetraalkylammonium hydrogensulphate, a tetraalkylammonium nitrate or a tetraalkylammoniumphosphate, more particularly a tetraalkylammonium hydrogen sulphate,most preferably tetra-n-butylammonium hydrogen sulphate.

The term “alkyl” as used above and hereinafter in connection with thephase transfer catalyst comprises straight-chain and branched alkylgroups with 1 to 8, preferably 2 to 6, more particularly 4 carbon atoms.Thus, preferred alkyl groups are the ethyl, n-propyl, i-propyl, n-butyl,2-butyl, tert-butyl, n-pentyl, 2-pentyl, neo-pentyl, n-hexyl and 2-hexylgroup. The n-butyl group is most particularly preferred.

Other preferred embodiments of the process according to the inventionare processes wherein:

(C) the diluent used is an aromatic hydrocarbon, preferably benzene,toluene or xylene, particularly toluene, or an optionally halogenatedaliphatic hydrocarbon, preferably dichloromethane, chloroform, carbontetrachloride or dichloroethane, particularly dichloromethane;

(D) the reaction is carried out in a temperature range from −10° C. to+30°, preferably from 0° C. to 28° C., particularly from 20 to 25° C.;

(E) the 4-phenylbutanol is added within 10 to 240 minutes, preferably 15to 60 minutes, and the resulting reaction mixture is stirred for afurther 30 to 180, preferably 45 to 150 minutes;

(F) 0.75 to 2.5 equivalents, preferably 1.5 to 2.2 equivalents, moreparticularly about 2 equivalents of 1,6-dibromohexane are used, based on1 equivalent of 4-phenylbutanol;

(G) 2.5 to 5.5 equivalents, preferably 2.8 to 5.2 equivalents, moreparticularly 3.0 to 4.0 equivalents of base are used, based on 1equivalent of 4-phenylbutanol;

(H) 0.01 to 0.5 equivalents, preferably 0.02 to 0.2 equivalents, moreparticularly 0.05 to 0.15 equivalents of phase transfer catalyst areused based on 1 equivalent of 4-phenylbutanol;

(I) the mixture of 1,6-dibromohexane, a base, a phase transfer catalystand a diluent contains 1.5 to 4.0 parts by volume, preferably 2.0 to 3.0parts by volume, more particularly 2.2 to 2.8 parts by volume ofdiluent, based on 1 part by volume of 1,6-dibromoehexane;

(J) the mixture of 4-phenylbutanol and diluent contains 1.5 to 10 partsby volume, preferably 2.0 to 6.0 parts by volume, more particularly 3.0to 5.0 parts by volume of diluent, based on 1 part by volume of4-phenylbutanol;

(K) after the reaction has ended water is added to the reaction mixture,the phases are separated, the organic phase is washed with water,concentrated under reduced pressure and the residue is fractionallydistilled under a high vacuum.

In a particularly preferred embodiment 1 equivalent of 4-phenylbutanolin about twice the volume of toluene is metered, within 10 to 60minutes, into a mixture of about 2 equivalents of 1,6-dibromohexane, 3to 5 equivalents of KOH, about 0.1 equivalents of tetra-n-butylammoniumhydrogen sulphate and 4 to 6 times the volume of toluene, based on thevolume of 4-phenylbutanol, at a temperature between 20 and 30° C., withstirring. After it has all been added the mixture is rinsed with tolueneand stirred for 90 to 360, preferably about 180 to 240 minutes at atemperature between 20 and 30° C. Then water is added, the organic phaseis separated off and washed with water. The organic phase isconcentrated and the residue is fractionally distilled under a highvacuum.

Further advantageous aspects of the procedure according to the inventionare the high space-time yield of the present process as well as the highyield and purity of 4-(6-bromohexyloxy)-butylbenzene, which can befurther processed directly or after distillation to form salmeterol.

Starting from the 4-(6-bromohexyloxy)-butylbenzene prepared by theprocess according to the invention, salmeterol is prepared in a mannerknown per se as described, for example, in DE 34 14 752 or EP 1 132 373.

The following Examples serve to illustrate some processes carried out byway of example for preparing 4-(6-bromohexyloxy)-butylbenzene. They areto be regarded merely as possible procedures described by way of examplewithout restricting the invention to their content.

EXAMPLE 1

4-(6-Bromohexyloxy)-butylbenzene

At a temperature between 20 and 25° C., with stirring, a mixture of247.5 ml (1.65 mol) of 4-phenylbutanol and 500 ml of toluene are addedwithin 45 minutes to a mixture of 509.6 ml (3.3 mol) of1,6-dibromohexane, 402 g of powdered (6.1 mol KOH) caustic potash, 5.6 g(0.165 mol) tetra-n-butylammonium hydrogen sulphate and 1250 ml oftoluene.

After it has all been added, the mixture is rinsed with 125 ml oftoluene and stirred for a further 2.5 hours at a temperature between 20and 25° C. Then 1875 ml of water are added, the organic phase isseparated off and washed twice with 1250 ml of water. The organic phaseis evaporated down under reduced pressure using the rotary evaporatorand the residue is fractionally distilled under a high vacuum (p<0.1mbar). 408.5 g (79% of theory) of the title compound are obtained as acolorless oil.

EXAMPLE 2

4-(6-bromohexyloxy)-butylbenzene

A mixture of 10 ml (0.0655 mol) of 4-phenylbutanol and 20 ml of tolueneis added within 15 minutes, with stirring, to a mixture of 20.2 ml(0.131 mol) of 1,6-dibromohexane, 16 g of powdered (0.242 mol KOH)caustic potash, 2.2 g (0.0066 mol) tetra-n-butylammonium hydrogensulphate and 50 ml of toluene, at a temperature between 25 and 30° C.After it has all been added the mixture is rinsed with 5 ml of tolueneand stirred for 2 hours at a temperature between 25 and 30° C. Then 75ml of water are added, the organic phase is separated off and washedtwice with 50 ml of water. The organic phase is concentrated underreduced pressure using the rotary evaporator and the residue isfractionally distilled under a high vacuum (p<0.1 mbar). 14.62 g (71% oftheory) of the title compound are obtained as a colorless oil.

COMPARISON EXAMPLE 1

4-(6-bromohexyloxy)-butylbenzene (corresponding to EP 1 132 373)

To a mixture of 5 ml (0.0323 mol) of 4-phenylbutanol and 10.1 ml (0.0657mol) of 1,6-dibromohexane are added, with stirring, 8 g of powdered(0.121 mol of KOH) caustic potash, whereupon the temperature rises toabout 30° C. Then 1.1 g (0.0033 mol) of tetra-n-butylammonium hydrogensulphate are added, whereupon the temperature rises to about 65° C.

After it has all been added the mixture is stirred for 20 hours atambient temperature. The reaction mixture is filtered, the filtrate istaken up in 50 ml of diethylether and 50 ml of water are added. Theorganic phase is separated off and dried. The organic phase isevaporated down under reduced pressure using the rotary evaporator andthe residue is fractionally distilled under a high vacuum (<0.1 mbar).5.8 g (56% of theory) of the title compound are obtained as a colourlessoil.

COMPARISON EXAMPLE 2

4-(6-bromohexyloxy)-butylbenzene

To a mixture of 20.2 ml (0.131 mol) of 1,6-dibromohexane, 16 g ofpowdered (0.242 mol KOH) caustic pot acid and 2.2 g (0.0066 mol) oftetra-n-butylammonium hydrogen sulphate are added 10 ml (0.0655 mol) of4-phenylbutanol within 15 minutes, with stirring, at a temperaturebetween 20 and 30° C. The reaction was spontaneously exothermic and thetemperature could hardly be controlled. Towards the end of the addition,hard lumps were formed and the reaction mixture was impossible to stir.

We claim:
 1. Improved process for preparing4-(6-bromohexyloxy)-butylbenzene comprised of the steps of reacting4-phenylbutanol with 1,6-dibromohexane in the presence of KOH and aphase transfer catalyst, wherein the 4-phenylbutanol in a diluent ismetered within 10 to 240 minutes into a mixture comprised of1,6-dibromohexane, a base, a phase transfer catalyst and a diluent andthe resulting reaction mixture is stirred for a further 30 to 180minutes and thereafter the 4-(6-bromohexyloxy)-butylbenzene product isisolated.
 2. Process according to claim 1, wherein the phase transfercatalyst is tetraalkylammonium or tetraalkylphosphonium salt.
 3. Processaccording to claim 1, wherein the phase transfer catalyst istetraalkylammonium hydrogen sulphate.
 4. Process according to claim 1,wherein the diluent is an aromatic hydrocarbon or an optionallyhalogenated aliphatic hydrocarbon.
 5. Process according to claim 1,wherein the diluent is toluene or dichloromethane.
 6. Process accordingto claim 1, wherein the reaction is carried out in a temperature rangefrom −10° C to +30° C.
 7. Process according to claim 1, wherein 0.75 to2.5 equivalents of 1,6-dibromohexane are used, based on 1 equivalent of4-phenylbutanol.
 8. Process according to claim 1, wherein 2.5 to 5.5equivalents of base are used, based on 1 equivalent of 4-phenylbutanol.9. Process according to claim 1, wherein 0.01 to 0.5 equivalents ofphase transfer catalyst are used, based on 1 equivalent of4-phenylbutanol.
 10. Process according to claim 1, wherein the mixtureof 1,6-dibromohexane, base, phase transfer catalyst and diluent contains1.5 to 4.0 parts by volume of diluent, based on 1 part of1,6-dibromohexane.
 11. Process according to claim 1, wherein the mixtureof 4-phenylbutanol and diluent contains 1.5 to 10 parts by volume ofdiluent, based on 1 part of 4-phenylbutanol.
 12. Process according toclaim 1, wherein after the reaction has ended water is added to thereaction mixture, the phases are separated, the organic phase is washedwith water, concentrated under reduced pressure and the residue isfractionally distilled under high vacuum.